1. Field of the Invention
The present invention describes novel phosphonate reagent compositions of the formula: ##STR4## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups or R, R'=(CH.sub.2).sub.n (n=2 or 3).
Allenic phosphonate reagent compositions (8) can be partially reduced to form allylic C-15 phosphonate compounds of the formula: ##STR5## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups.
Also described are methods of preparing a tertiary propargylic alcohol of the formula: ##STR6## (systematically named 3-(3-hydroxy-3-methylpent-1-en-4-ynyl)-2,4,4-trimethylcyclohex-2-en-1-one) , which can be used to prepare the phosphonate compositions (8) and (9).
2. Description of Related Art
(a) Utility and Preparation of Canthaxanthin
Of the approximately 600 naturally occurring carotenoids, only six are produced commercially. Although .beta.-carotene is the carotenoid with the strongest sales, during the past two decades production of astaxanthin (used in the "fish-farming" industry) and canthaxanthin (11) has rapidly increased. Canthaxanthin (11), which has been used in the poultry industry for several decades, was initially manufactured using a process that started with .beta.-carotene. Reference: R. Entschel and P. Karrer, Hely. Chim. Acta 1958, 41 402!. However, this type of approach to canthaxanthin is unattractive for several reasons: (a) the high cost of .beta.-carotene; (b) the large volume of solvents that are required when conducting reactions involving C-40 compounds; and, most importantly, the yield of canthaxanthin (based on the .beta.-carotene that is consumed) is moderate (50-65%) at best. For specific examples of this oxidative process, see German patent 2,534,805 (Feb. 10, 1977, issued to BASF) Chem. Abstracts 1977, 86, 155834z! and German patent 2,109,875 (Sep. 30, 1971, issued to Rhone-Poulenc) Chem. Abstracts 1972, 76, 4035g!.
By the early 1980's, the demand for canthaxanthin began to grow when various coaltar-based azo dyes were removed from the certified list of dyes permitted for use in foods and drugs. Canthaxanthin, which exhibits excellent tinctorial properties, was able to satisfy the need for a safe red coloring agent for human use.
An additional factor that could increase the market for canthaxanthin is its role in the chemoprevention of cancer. Recent studies in both mouse and human cells indicate that canthaxanthin can function in the post-initiation phase of carcinogenesis by suppressing the ability of carcinogen-initiated cells to undergo neoplastic transformation. Reference: J. S. Bertram, Pure & Appl. Chem., 1994, 66, 1025!.
In order to meet the demand for increased production of canthaxanthin, several convergent syntheses (i.e., routes involving the coupling of smaller fragments, each of which was synthesized independently) were developed. Among these routes, the most noteworthy one was developed at Hoffmann-La Roche. References: M. Rosenberger, et al., J. Org. Chem. 1982, 47, 2130; U.S. Pat. No. 4,000,198 (Dec. 28, 1976), which is cited in Chem. Abstracts 1977, 87, 39706f, and M. Rosenberger, et al., Pure & Appl. Chem. 1979, 51, 871!. The latter route involves a Wittig coupling of a C-15 phosphonium salt and the symmetrical C-10 dialdehyde (10) (2,7-dimethyl-2,4,6-octatrienedial) to generate canthaxanthin. Although employing straightforward chemical operations, this approach suffers from the use of a costly raw material (triphenylphosphine) as well as too many steps (approximately 13 reactions are required to construct the C-15 phosphonium salt). Researchers at Hoffmann-La Roche K. Bernhard and H. Mayer, Pure & Appl. Chem. 1991, 63, 35! have recently indicated that this last step is a problem for the manufacture of canthaxanthin and related polyenes: "A major drawback of this olefination reaction, however, is the formation of triphenylphosphine oxide which, on an industrial production scale, has to be recycled by reduction to triphenylphosphine. Any type of synthesis which circumvents problems of that kind is of potential value in large scale synthesis of polyenes."
Another route to canthaxanthin involves a ten-step process starting with .alpha.-ionone (3) and the symmetrical dialdehyde 10. Reference: K. Bernhard and H. Mayer, Pure & Appl. Chem. 1991, 63, 35!. A major disadvantage to this route is the fact that two chemical transformations have to be conducted after the C-40 skeleton of canthaxanthin has been obtained by coupling a C-15 sulfone intermediate to the C-10 dialdehyde 10. Difficulties associated with performing chemical transformations at the C.sub.40 level include solubility problems and the intrinsic instability of polyene compounds.
(b) Preparation of Tertiary Propargylic Alcohol
A tertiary propargylic alcohol of the following formula: ##STR7## can be used to prepare the novel C-15 allenic phosphonate reagent compositions (8) and C-15 allylic phosphonate compounds (9). Tertiary propargylic alcohol (7) can prepared in four steps from .alpha.-ionone (3), according to the following reaction sequence: ##STR8##
Alternatively, tertiary propargylic alcohol (7) can prepared in three steps from .beta.-ionone (12), according to the following reaction sequence: ##STR9## Reference for the conversion of (12) to (14): Japanese patent 81,161,370 (Dec. 11, 1981); Chem. Abstracts 1982, 96, 199941t.
Both .alpha.-ionone (3) (used in Scheme I) and .beta.-ionone (12) (used in Scheme II) are obtained in high yield in two-step processes that start with citral (1). Reference: H. Hibbert and L. T. Cannon, J. Am. Chem Soc. 1924, 46, 119!. It should be noted that all of the above-described transformations for preparing tertiary propargylic alcohol (7) involve straightforward chemical operations and low-cost raw materials. Furthermore, most of these transformations have previously been conducted on a large scale and been shown to afford good yields of the desired products. For example, .alpha.-ionone (3) can be converted to epoxide (4) in 98% yield D. W. Brooks and E. Kennedy, J. Org. Chem., 1983, 48, 277!; and the latter epoxide has been converted in 99% yield to hydroxy ketone (5) M. Rosenberger, et al., J. Org. Chem. 1982, 47, 2130!. In addition to citral (1) and acetone, the only organic raw material required to synthesize tertiary propargylic alcohol (7) is acetylene.